1. Field of the Invention
The present invention relates to bone cements and, more particularly, to acrylic-based (i.e., the use of polymers and monomers based on methacrylic acid) orthopedic bone cements, their use in spinal applications, and methods for making the same.
2. Description of the Related Art
The clinical use of total joint replacements in the United States is expected to rise precipitously over the next twenty-five years, projected to the level of over 4 million primary total knee and hip replacement procedures performed annually by the year 2030. The number of revision surgeries for both total hips and total knees will likely double over this time period as well. Thus, the demand for high performance bone cement is rapidly growing.
One of the critical factors in the clinical success of total joint arthroplasty is stable fixation of the prosthesis; which, in a majority of cases, is accomplished through the application of PMMA-based bone cement. While bone cement has been used clinically since the early 1960's and there are many commercially available powder-liquid cement compositions, the material continues to be scrutinized for the role that it plays in aseptic loosening of total joint prostheses.
Multi-solution acrylic bone cements (typically referred to as a two-solution bone cement, but which could have more than two solutions) have surfaced as an alternative to powder-liquid cement, using the same chemical constituents as current commercial formulations. This cement consists of PMMA powder pre-dissolved in methyl methacrylate (MMA) monomer, to form two separate solutions; one containing the initiator, benzoyl peroxide (BPO) and the other containing the activator, N,N-dimethyl-p-toluidine (DMPT), which react to initiate polymerization of the MMA when the solutions are mixed. These solutions have an initial viscosity similar to that of powder-liquid cement in the dough stage, therefore they can be simultaneously mixed and delivered to the surgical site via a single, closed system. This not only simplifies the surgical procedure by eliminating the multi-stage process of cement mixing and delivery, but also reduces the extent to which the properties of the polymerized cement depend on variations in surgical technique. Two-solution bone cement compares favorably to commercial cements (Simplex P and Palacos R) both in its mechanical properties and biocompatibility.
While the two-solution bone cement concept is a promising alternative to powder-liquid cements, it has several drawbacks in its current form, primarily related to the increase in monomer concentration necessary to form viscous solutions of dissolved linear PMMA. Many important properties of the cement, including the polymerization exotherm, residual monomer concentration, volumetric shrinkage, and shrinkage-induced porosity, are directly proportional to the initial monomer concentration. These properties represent the key areas where two-solution cement currently does not perform as well as commercial powder-liquid cements. The reduction of monomer in two-solution bone cement is limited by the solution viscosity, which is controlled by both the concentration and molecular weight (MW) of the PMMA in solution. Increasing the P:M ratio, without decreasing the MW of the PMMA, increases solution viscosity, yielding cements, which are difficult to mix and deliver. Significantly decreasing the PMMA MW in order to increase the P:M ratio, however, leads to a marked decrease in the mechanical properties of the polymerized cement.
Poly (methyl methacrylate) bone cements have primarily evolved for the fixation of total hip and knee joint arthroplasties. Over 30 commercially available plain acrylic cement brands are currently approved for use in cemented arthroplasties. Some of these commercial cements have been tailored recently for the treatment of vertebral compression fractures using kyphoplasty (KP) and vertebroplasty (VP) procedures. Percutaneous VP and KP stabilize vertebral compression fractures resulting from osteoporosis and other lesions. Both procedures involve injection of modified formulations of bone cements into the fractured vertebrae in order to restore functionality and reduce pain. The desirable properties of injectable bone cements for the treatment of vertebral compression fractures (using VP and KP procedures) comprise high radiopacity, suitable viscosity to allow easy handling and injectability, high compressive strength, low curing temperature and longer setting times (e.g., about 15 minutes and mechanical properties resembling those of non-osteoporotic vertebrae). Currently, no standardized formulations meet the viscosity criteria for use in the spine. Therefore in order to lower viscosity and increase the working time of commercial cements, surgeons usually alter the polymer-to-monomer ratio recommended by manufacturers. Lower viscosities are desirable to enhance penetration of the cement into the small pores of the cancellous bone, thereby increasing the strength of the interface between bone and cement mantle. Likewise, lower exotherm temperatures may provide protection from heat damage, avoiding thermal necrosis of surrounding soft tissues. Formulations that set more slowly would allow not only extended time for heat dissipation, but also better workability and handling.
Standard two-solution bone cement (STBC, as described in U.S. Pat. No. 5,902,839) has emerged as an alternative to current powder-liquid formulations. According to studies carried out by Hasenwinkel et al (cited below) the standard two-solution cement has the advantage of being porosity free and have higher flexural strength and modulus of elasticity. One limitation of this material is the high initial viscosity of the dough, which makes injection of the cement through small needles and cannulas difficult. STBC has the advantage of presenting higher flexural strength and modulus of elasticity, being less porous than commercial formulations. It also has the advantage of being mixed in a simpler manner, which allows metered delivery of material in a closed system (see Hasenwinkel J M, Lautenschlager E P, Wixson R L, Gilbert J L, A novel high-viscosity, two-solution acrylic bone cement: effect of chemical composition on properties, J. Biomed Mater Res 1999; 47:36-45; and Hasenwinkel J M, Lautenschlager E P, Wixson R L, Gilbert J L, Effect of initiation chemisty on the fracture toughness, fatigue strength, and residual monomer content of a novel high-viscosity, two-solution acrylic bone cement, J Biomedical Materials Research 2002; 59, 411-421). However, one limitation of the use of this formulation in KP and VP is the higher initial viscosity of the cement and relatively short setting time (varying from 7 to 9 minutes from the beginning of mixing).
It is well known that acrylic bone cements are non-Newtonian or pseudoplastic fluids that undergo shear thinning with increasing shear rates, presenting significant differences in the flow behavior among compositions. The clinical significance of highly pseudoplastic cements is related to the fact that the material can be subjected to rapid thinning, which consequently enhances flow through a delivery system and into the interstices of the bone. Another important factor affecting viscosity of bone cements is the incorporation of polymer particles or fillers in the cement matrix. Polymer particle size and its distribution (polydispersity), volume fraction and particle-particle interaction are factors that determine the rheological behavior of dispersed systems. Even though the effects of the size and size distribution of PMMA particles on the properties of acrylic bone cements are discussed in the literature, most of these studies involved the application of commercial samples of linear PMMA used in powder-liquid formulations. For example, Pascual et al showed that the use of PMMA particles with average diameter in the 50-60 μm range and with wide size distribution significantly changed the maximum polymerization exotherm and setting characteristics of cement formulations (see Pascual B, Vazquez B, Gurruchaga M, Goni I, Ginebra M P, Gil F J, Planell J A, Levenfeld B, Roman J S, New aspects of the effect of size and size distribution on the setting parameters and mechanical properties of acrylic bone cements, Biomaterials 1996; 17:509-516). Likewise, Hernandez et al discussed the influence of powder size distribution on the properties of cements used in KP and VP showing that cements with a high proportion of large PMMA beads (˜118 μm) to small beads (˜70 μm) presented suitable viscosity behavior and injectability (see Hernandez L, Gurruchaga M, Goni I, Influence ofpowder particle size distribution on complex viscosity and other properties of acrylic bone cement for vertebroplasty and kyphoplasty, J Biomed Mater Res B: Appl Biomater 2006; 77B:98-103).
The application of acrylic bone cement for the treatment of vertebral compression fractures requires visualization of the material flow under image fluoroscopy. In order to enhance contrast, it is common practice to alter the composition of commercial cements by increasing the amount of radiopacifier. Radiopacity of the cements is achieved by the addition of contrast radiopacifier materials, such as BaSO4 and ZrO2, which are vastly discussed in the literature to cause alterations in the biological and mechanical properties of cements. The effect of BaSO4 on the static and dynamic properties of bone cements is somewhat contradictory. Most studies have reported deleterious effects of BaSO4 in the mechanical performance of cements due to clumping resulting from the heterogeneity and incompatibility of the polymeric matrix and inorganic salt. For example, Wang et al pointed out that the addition of BaSO4 to Simplex P lowers the ultimate tensile strength and fracture toughness of the material (see Wang C T, Pilliar R M, Fracture toughness ofacrylic bone cements, J Mater Sci 1989; 24:3725-38). Ginebra et al showed a similar trend in tensile strength by the presence of BaSO4 in comparison to a radiolucent cement (see Ginebra M P, Albuixech L, Fernandez-Barragan E, Aparicio C, Gil F J, San Roman J, Vazquez B, Planell J A, Mechanical performance of acrylic bone cements containing different radiopacifying agents, Biomaterials 23; 2002:1873-1882). On the contrary, Kurtz et al and Jasper et al reported a significant increase in the compressive properties as a function of increasing BaSO4 content (see Kurtz S M, Villarraga M L, Zhao K, Edidin A A, Static and fatigue mechanical behavior of bone cement with elevated barium sulfate content for treatment of vertebral compression fractures, Biomaterials 2005; 26:3699-3712; Jasper L E, Deramond H, Mathis J M, Belkoff S M, Material properties of various cements for use with vertebroplasty, J Mater Sci: Mater Med 2002; 13:1-5). Vallo et al reported that the presence of radiopacifier fillers improved fracture toughness by promoting interactions between the crack and the second phase dispersion, and Deb el al concluded that the presence of the inorganic phase did not seem to affect the tensile strength of acrylic cements (see Vallo C I, Cuadrado T R, Frontine P M, Mechanical and fracture behavior evaluation of commercial acrylic bone cements, Polym Int 1997; 43:260-268; Deb B and Vazquez B, The effect of cross-linking agents on acrylic bone cements containing radiopacifiers, Biomaterials 2001; 22:2177-2181). In view of these contradictory opinions, alternative radiopacifiers and methods have been explored, as for example, the use of tantalum-based cements, iodine containing monomers and substitution of ZrO2 for BaSO4, which seems to have less detrimental effects due to the size and morphology of the particles that allow for better adhesion within the matrix. Current commercial cements that utilize ZrO2 include Palacos R (Zimmer, Inc.).
Description Of the Related Art Section Disclaimer: To the extent that specific publications are discussed above in this Description of the Related Art Section, these discussions should not be taken as an admission that the discussed publications are prior art for patent law purposes. For example, some or all of the discussed publications may not be sufficiently early in time, may not reflect subject matter developed early enough in time and/or may not be sufficiently enabling so as to amount to prior art for patent law purposes. To the extent that specific publications are discussed above in this Description of the Related Art Section (as well as throughout the application), they are all hereby incorporated by reference into this document in their respective entirety(ies).